Early detection and management of shock are important in optimizing clinical outcomes. One regional marker, sublingual capnography (SLCO2), is particularly appealing as redistribution of blood flow away from the sublingual mucosa can happen very early in the compensatory phase of hypovolemic shock. Our objective was to test the hypothesis that SLCO2 would detect early hypovolemia in a human laboratory model of hemorrhage: progressive lower body negative pressure until onset of cardiovascular collapse. Eighteen healthy nonsmoking subjects (10 males, 8 females) with mean age of 28 (SD, 8) years, body weight of 72 (SD, 13) kg, and height of 172 (SD, 9) cm were recruited to participate, of whom 17 completed the experiment. Average time to presyncope was 1,579 ± 72 s (mean ± SE). At the time of cardiovascular collapse, lower body negative pressure altered (P < 0.001) systolic blood pressure (mean ± SE: 130 ± 3 vs. 98 ± 2 mm Hg), pulse pressure (mean ± SE: 58 ± 2 vs. 33 ± 2 mm Hg), and heart rate (mean ± SE: 63 ± 3 vs. 102 ± 6 beats/min) when compared with baseline, whereas SLCO2 did not change (49.1 ± 1.0 vs. 48.6 ± 1.5 mm Hg, P = 0.624). In a model of progressive central hypovolemia in humans, we did not detect metabolic derangements in the sublingual mucosa as measured by SLCO2.